Acquired and inherited skin blistering diseases are debilitating, life-altering illnesses. Many of these diseases are caused by a loss of desmosome function. Our ability to understand and design treatments for these diseases is hindered by our relatively poor understanding of basic desmosome biology. Very little is currently known about the regulation of desmosome assembly, or the means by which assembly becomes misregulated in various skin diseases. Data from our lab and others suggest desmosomes are assembled in microdomains of the plasma membrane known as lipid rafts. In order to understand the role that lipid rafts play in desmosome biology, we are examining the consequences of lipid raft association on the desmosomal cadherins known as desmogleins. We hypothesize that the desmoglein transmembrane domain targets this protein to lipid rafts, and that lipid raft association is necessary for incorporation into desmosomes and adhesive function. In our first aim, we will determine the role of lipid raft association in desmoglein function. In our second aim, we will determine how a mutation in the transmembrane domain of a desmoglein causes a human skin disease. Our long-term goal is to understand the mechanisms involved in regulating desmosomes and to identify new targets for potential intervention in pathogenesis. Resolving the mechanisms governing desmosome assembly would constitute an important advance in our understanding of cell-cell adhesion. This advance will also pave the way for new therapeutic strategies for treating an array of human skin diseases stemming from desmosomal misregulation.